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DOI: 10.1055/s-0038-1657783
New Anticoagulant Agents: Incidence of Adverse Drug Reactions and New Signals Thereof
Publication History
Publication Date:
04 June 2018 (online)
![](https://www.thieme-connect.de/media/sth/201902/lookinside/thumbnails/10-1055-s-0038-1657783_02550-1.jpg)
Abstract
The aim of this study was to evaluate the adverse drug reaction (ADR) incidence rate and new signals thereof for classic compared with new anticoagulants in real-life ambulatory settings. The authors performed an observational cross-sectional study in two cohorts of surveyed patients treated with vitamin K antagonists (VKAs; acenocoumarol or warfarin) or nonvitamin K antagonist oral anticoagulants (NOACs; apixaban, edoxaban, rivaroxaban, dabigatran etexilate). Descriptive, clinical, and ADRs data were reported and analyzed through a bivariate analysis (odds ratio [OR]) to compare the ADRs incidence rate and an adaptation of Bayesian methodology (false discovery rate [FDR] < 0.05) to detect new signals. A total of 334 patients were surveyed—average international normalized ratio (INR) of 2.6—and 45.4% taking new anticoagulants. Note that 835 ADRs were reported; 2.5 per patient (2.8 in the VKA cohort, 2.1 in the NOAC cohort). The authors obtained higher risk of epistaxis (OR, 2.18; 95% confidence interval [CI], 1.01–4.74) and hematoma (OR, 2.43; 95% CI, 1.39–4.25) with VKAs and lower risk of global bleeding symptoms with NOACs (OR, 0.45; 95% CI, 0.28–0.71). After standardizing the data, a significant risk of diarrhea with VKAs was observed (OR, 3.37; 95% CI, 1.09–10.41). They also detected an intense positive signal regarding the use of VKAs and osteoporosis (FDR < 0.001), specifically acenocoumarol (FDR < 0.002). NOACs presented lower risk of bleeding, especially dabigatran (FDR < 0.031), and of dermatological pathologies with apixaban being the safest (FDR = 0.050). The lower risk of global bleeding and a potential protective effect against osteoporosis in patients treated with NOACs postulate them as safer than VKAs.
Grant Support
The Sentinel network in Castilla y León received financial support from Daiichi Sankyo España S.A.U. to assume the administrative cost of the project.
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References
- 1 Portal estadístico del Ministerio de Sanidad, Servicios Sociales e Igualdad. Gobierno de España. Tasas de mortalidad ajustadas por edad a partir de; 1999. Ministerio de Sanidad, Servicios Sociales e Igualdad. Available at: http://pestadistico.inteligenciadegestion.msssi.es/publicoSNS/ comun/Informe.aspx?IdNodo=5012 . Accessed February 15, 2017
- 2 de Abajo F, García J. Utilización De Antiagregantes Y Anticoagulantes En España (1992–2006). Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Available at: https://www.aemps.gob.es/medicamentos UsoHumano/observatorio/docs/antiagregantes.pdf . Accessed December 15, 2017
- 3 Franchini M, Liumbruno GM, Bonfanti C, Lippi G. The evolution of anticoagulant therapy. Blood Transfus 2016; 14 (02) 175-184
- 4 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
- 5 Connolly SJ, Ezekowitz MD, Yusuf S. , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
- 6 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
- 7 Granger CB, Alexander JH, McMurray JJV. , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
- 8 Hori M, Matsumoto M, Tanahashi N. , et al; J-ROCKET AF study investigators. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation – The J-ROCKET AF study. Circ J 2012; 76 (09) 2104-2111
- 9 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
- 10 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
- 11 Carvajal A, Sáinz M, Velasco V. , et al. Emergency contraceptive pill safety profile. Comparison of the results of a follow-up study to those coming from spontaneous reporting. Pharmacoepidemiol Drug Saf 2015; 24 (01) 93-97
- 12 Bate A, Lindquist M, Edwards IR. , et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 1998; 54 (04) 315-321
- 13 Vega Alonso AT, Zurriaga Llorens O, Galmés Truyols A. , et al; Group of Research for the RECENT Project. Health sentinel networks in Spain. Consensus for a guide of principles and methods [in Spanish]. Gac Sanit 2006; 20 (06) 496-502
- 14 Ahmed I, Haramburu F, Fourrier-Réglat A. , et al. Bayesian pharmacovigilance signal detection methods revisited in a multiple comparison setting. Stat Med 2009; 28 (13) 1774-1792
- 15 Gould AL. Practical pharmacovigilance analysis strategies. Pharmacoepidemiol Drug Saf 2003; 12 (07) 559-574
- 16 Nóren N. . ed. A Monte Carlo Method for Bayesian Dependency Derivation . Gothenburg: Chalmers University of Technology; 2002
- 17 Adelborg K, Grove EL, Sundbøll J, Laursen M, Schmidt M. Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies. Heart 2016; 102 (23) 1883-1889
- 18 de Abajo F, García del Pozo J. Utilización De Antiagregantes Y Anticoagulantes En España (1992–2006). Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) [Internet]; 2006. Available at: https://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/antiagregantes.pdf . Accessed December 28, 2016
- 19 Catalá-López F, Tobías A. Meta-analysis of randomized trials, heterogeneity and prediction intervals [in Spanish]. Med Clin (Barc) 2014; 142 (06) 270-274
- 20 Bahit MC, Lopes RD, Wojdyla DM. , et al. Non-major bleeding with apixaban versus warfarin in patients with atrial fibrillation. Heart 2017; 103 (08) 623-628
- 21 Sauter TC, Hegazy K, Hautz WE. , et al. Epistaxis in anticoagulated patients: Fewer hospital admissions and shorter hospital stays on rivaroxaban compared to phenprocoumon. Clin Otolaryngol 2017; ; Epub ahead of print DOI: 10.1111/coa.12904.
- 22 Gökdoğan O, Akyildiz I, Sayin BY, Okutucu S, Tanalp AC, Arslan N. The Rate of epistaxis incidence in new-generation anticoagulants and perioperative approach in otorhinolaryngological practices. J Craniofac Surg 2017; 28 (02) e178-e182
- 23 Roux E, Thiessard F, Fourrier A, Bégaud B, Tubert-Bitter P. Evaluation of statistical association measures for the automatic signal generation in pharmacovigilance. IEEE Trans Inf Technol Biomed 2005; 9 (04) 518-527
- 24 Bate A, Lindquist M, Edwards IR. The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database. Fundam Clin Pharmacol 2008; 22 (02) 127-140
- 25 Bate A. Bayesian confidence propagation neural network. Drug Saf 2007; 30 (07) 623-625
- 26 Bate A, Lindquist M, Orre R, Edwards IR, Meyboom RH. Data-mining analyses of pharmacovigilance signals in relation to relevant comparison drugs. Eur J Clin Pharmacol 2002; 58 (07) 483-490
- 27 Zorych I, Madigan D, Ryan P, Bate A. Disproportionality methods for pharmacovigilance in longitudinal observational databases. Stat Methods Med Res 2013; 22 (01) 39-56
- 28 Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009; 18 (06) 427-436
- 29 Lindquist M, Ståhl M, Bate A, Edwards IR, Meyboom RH. A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database. Drug Saf 2000; 23 (06) 533-542
- 30 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Sintrom® SPC [Internet]; 2017. Available at: https://www.aemps.gob.es/cima/dochtml/ft/58994/ FichaTecnica_58994.html . Accessed August 15, 2017
- 31 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Xarelto® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document library/EPAR_Product_Information/human/000944/WC500057108.pdf . Accessed August 15, 2017
- 32 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Lixiana® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library /EPAR_-_Product_Information/human/002629/WC500189045.pdf . Accessed August 15, 2017
- 33 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Eliquis® SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library/ EPAR_-_Product_Information/human/002148/WC500107728.pdf . Accessed August 15, 2017
- 34 Agencia Española de Medicamentos y Productos Sanitarios (AEMPS). Centro de Información online de Medicamentos de la AEMPS-CIMA. Ministerio de Sanidad, Servicios Sociales e Igualdad. Pradaxa SPC [Internet]; 2017. Available at: http://www.ema.europa.eu/docs/es_ES/document_library/ EPAR_-_Product_Information/human/000829/WC500041059.pdf . Accessed August 15, 2017
- 35 Namba S, Yamaoka-Tojo M, Hashikata T. , et al. Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis. BBA Clin 2015; 4: 76-80
- 36 Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 2006; 166 (02) 241-246
- 37 Iwamoto J. Vitamin K2 therapy for postmenopausal osteoporosis. Nutrients 2014; 6 (05) 1971-1980
- 38 Namba S, Yamaoka-Tojo M, Kakizaki R. , et al. Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation. Heart Vessels 2017; 32 (08) 977-982
- 39 Lau WC, Chan EW, Cheung CL. , et al. Association between dabigatran vs warfarin and risk of osteoporotic fractures among patients with nonvalvular atrial fibrillation. JAMA 2017; 317 (11) 1151-1158